Commonwealth of Australia 2002
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- 10.4Long-term exposure
- 10.4.2Chronic exposure and carcinogenicity
- 10.5Genotoxicity and related end points
10.3Short-term exposureIncreases in hepatic cytochrome P 450 content have been observed in female rats administered limonene (isomer unspecified; 40 mg/kg bw/d for 3 days) by intraperitoneal injection *(Austin et al., 1988) and in rats administered 5% d limonene in the diet for 2 weeks *(Maltzman et al., 1991). Increased epoxide hydratase activity was observed in rats administered 1% or 5% d-limonene in the diet for 2 weeks *(Maltzman et al., 1991). Increases in phase II enzymes (glutathionyltransferase and UDP glucuronyltransferase) during the exposure of rats to 5% limonene in food have also been described *(Maltzman, 1991). Increased relative liver weight (from 5 to 20 times) has been observed in rats administered d-limonene at a dose of 75 300 mg/kg bw, at 300 mg/kg bw, the increase was significant *(Kanerva et al., 1987). In cats, infusion of 97% d limonene into the bile system to dissolve gallstones caused acute and chronic inflammatory changes *(Schenk et al., 1980). 10.4Long-term exposure10.4.1Subchronic exposurePeroral administration of d-limonene to rats at a dose of 400 mg/kg bw for 30 d resulted in a 20 30% increase in the amount and activity of different liver enzymes (cytochrome P 450, cytochrome b5, aminopyrine demethylase, and aniline hydroxylase), increased relative liver weight, and decreased cholester ol levels *(Ariyoshi et al., 1975). Administration of d- limonene (0, 2, 5, 10, 30, and 75 mg/kg bw/d) by gavage to groups of 10 male rats, 5 d/week for 13 weeks *(Webb et al., 1989), resulted in the patho logical formation of granular casts at the outer zone of the renal medulla. The no-observed-effect level (NOEL), based upon histological examination of the kidneys, was considered to be 5 mg/kg bw/d. The LOEL for increased liver and kidney weight was 75 mg/kg bw/d, the highest dose tested. The NOEL for effects in the liver was 10 mg/kg bw; the no-observed-adverse-effect level (NOAEL) for effects in the liver was 30 mg/kg bw/d. Linear regression analysis revealed a dose-related trend in the increased relative weights of the kidney and liver at 30 and 75 mg/kg bw/d. No histopathological changes were observed in the liver in these two studies. The amount and activity of different liver enzymes were not investigated, and thus the increase in relative liver weight may be due to enzyme induction. It is considered that the observed effects in the liver are probably signs of a physiological adaptation (Karlberg & Lindell, 1993). 10.4.2Chronic exposure and carcinogenicityThe oral administration of d limonene (0.4, 1.2, or 3.6 ml/kg bw/d) to dogs for 6 months caused nausea and vomiting *(Tsuji et al., 1975a). A 35% increase in alkaline phosphatase and cholesterol in serum and slightly increased total and relative liver weights were observed in dogs after peroral administra tion of d limonene at a dose of 1.2 ml/kg bw/d for 6 months (about 1000 mg/kg bw/d) *(Webb et al., 1990). In a 2 y study, d limonene was administered (per os) 5 d/week to groups of 50 F344/N rats (0, 75, or 150 mg/kg bw/d to males, and 0, 300, or 600 mg/kg bw/d to females) and B6C3F mice (0, 250, or 500 mg/kg bw/d to males, and 0, 500, or 1000 mg/kg bw/d to females) (NTP, 1990). Slightly lower body weights were observed for rats in the high dose groups and female mice in the high dose group; however, no clinical symptoms could be related to the administration of d-limonene. For female rats in the high dose group, survival was reduced after 39 weeks (NTP, 1990). There was clear evidence of carcinogenic activity of d-limonene in male rats, based upon a dose related increase in the incidence of hyperplasia and adenoma/ adenocarcinoma in renal tubular cells. However, there was no evidence of carcinogenicity in female rats or in male and female mice. The carcinogenic response in the kidney of male rats has been linked to a unique renal perturbation involving 2 globulin. To determine whether d limonene would cause a sustained increase in renal cell proliferation and exhibit promoting activity for the development of renal adeno mas in male F344 rats, the animals were administered (by stomach tube) d limonene (150 mg/kg bw/d) as a promoter 5 d/week for 30 weeks *(Dietrich & Swenberg, 1991). N ethyl N hydroxyethyl -nitrosamine (500 ppm) (2780 mg/m3) (was used as an initiator in the drinking water for 2 weeks. In addition, male 2- globulin deficient rats were exposed in the same manner to determine if the mate rat specific urinary protein 2- globulin is required for d limonene to cause these effects. Exposure to d limonene alone caused a significant increase in the number of atypical tubules and atypical hyperplasias in F344 rats, compared with vehicle controls. There was no increase in the incidence of tumours or preneoplastic lesions in the 2 globulin deficient rats exposed to d limonene, whereas a 10 fold increase in the incidence of renal adenoma and atypical hyperplasia was observed in F344 rats exposed to d- limonene compared with controls. There was a signifi cant decrease in the incidence of liver tumours in animals exposed to N ethyl N hydroxyethylnitrosamine and d-limonene, compared with N ethyl N hydroxy ethylnitrosamine exposure alone.
No evidence of mutagenicity was reported in an in vivo spot test with mice, involving the intraperitoneal injection of limonene at 215 mg/kg bw/d on days 9 11 during gestation *(Fahrig, 1984). Directory: data -> assets -> word doc -> 0019 0019 -> Commonwealth of Australia 2000 0019 -> Rail safety news issue 6 – October 2011 0019 -> Social and economic benefits of improved adult literacy: Towards a better understanding Robyn Hartley Jackie Horne 0019 -> From: Virginia Holt [mailto: (personal contact details deleted) 0019 -> By Yvonne Hillier Introduction 0019 -> Communications alliance 0019 -> Allocations Manual Homeless with Support Category 0019 -> Inquiry into Vulnerable Road Users Inquiry into Vulnerable Road Users Download 1.1 Mb. Share with your friends:
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